Impurity Profiling: A Case Study of Ezetimibe

Abstract

Impurity profiling includes a description of the identified and unidentified impurities present in new drug substances or drug products. Isolation and elucidation of the structures of degradation products are typically collaborative research involving knowledge of analytical, organic and physical chemistry with spectroscopic information. Stability testing guidelines issued by International Conference on Harmonization (ICH) require the reporting, identification and characterization of degradation products (DPs). The alkaline degradant was detected by high performance liquid chromatography (HPLC) at relative retention time (RRT) of 1.48 with respect to Ezetimibe. This degradant was isolated by preparative HPLC. Purity of the isolated solid was found to be more than 99%. Structure of alkaline degradant was confirmed by LC-MS, 1 H and 13 C NMR and IR spectroscopy. On the basis of spectral data, the structure of the degradant was confirmed as 5-(4-fluorophenyl)-2-[(4-fluorophenyl amino)-(4-hydroxyphenyl)methyl]-pent-4-enoic acid. An understanding of the parts of the molecule that are susceptible to degradation can help in the design of more stable analogs. Determining the structures of the major degradation products can reveal whether or not a known carcinogen or toxic compound is or might possibly be formed.

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“…Ezetimibe (EZE), a selective inhibitor of intestinal cholesterol and related phytosterol absorption, is designated as1-(4fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl) -2-azetidinone Figure 1, It blocks the intestinal absorption of dietary and biliary cholesterol, without affecting the uptake of triglycerides or fat soluble vitamins, this reduce the overall delivery of cholesterol to the liver, thereby promoting the synthesis of LDL receptors and a subsequent reduction in serum LDL-C [1][2][3][4][5][6][7]. The literature is enriched with several techniques for determination of (EZE) in pharmaceutical dosage forms and/or biological fluids, including HPLC methods for the determination of ezetimibe are reported , TLC [15,18,[32][33][34][35][36][37], LC [38][39][40][41][42][43][44][45], chemometry [32,46], Spectrophotometric methods [13,30,31,, UPLC [69,70], densitometry [54,71], electrokinetic chromatography [72], electrophoresis [73], voltammetry [74], spectrofluorometry [75], other related with degradation and elucidation of alkaline degradate of ezetimibe [76][77][78].…”

An Experimental Design Approach for Impurity Profiling of Valacyclovir-Related Products by RP-HPLC

“…Impurity profiling is a broad term which encompasses the identification, quantitative determination, and structural elucidation of impurities with the aid of spectroscopy or chromatographic techniques or the utilizations of the latest developed hyphenated methods [ 1 , 2 ]. Quality is an essential attribute in any pharmaceutical product, which is greatly determined by the content of the active ingredient present in it whatever its source or origin and the techniques adopted for its synthesis or formulation.…”

“…Quality is an essential attribute in any pharmaceutical product, which is greatly determined by the content of the active ingredient present in it whatever its source or origin and the techniques adopted for its synthesis or formulation. In the pharmaceutical world, impurities are considered as any material other than the active pharmaceutical ingredient (API) or excipients; may it be of organic or inorganic origin, may it arise from varied sources like process-related drug substances (starting material, intermediate, or drug product), an impurity in starting materials, degradation of drug substances, unwanted excipient-interactions, contaminations of some reagents and catalysts, presence of enantiomeric impurities, and some impurities may be due to environmental factors [ 1 – 6 ]. The presence of these unwanted chemicals, even in small amounts, may influence the efficacy and safety of the pharmaceutical products and can precipitate adverse and toxic drug reactions in patients after consumption.…”

“…With the tremendous advancements of analytical technologies and changed perspectives of the research scenario, not only detection of active constituents, but a detailed profiling of impurities offers a broad scope of research in pharmaceutical and other bio-allied fields. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has also published guidelines for the validation of methods for analysing impurities in new drug substances and drug products, residual solvents, and microbiological impurities [ 1 , 2 ]. ICH defines an impurity as “any chemical compound of the medicinal product which is not the chemical entity defined as the active substance or as an excipient in the product.” According to its guidelines, the threshold limit for any impurity is at 0.1% for drugs used in dosages more than 2 g/day and for those dosed at less than 2 g/day, the limit is below 0.05% [ 2 , 6 , 6 ].…”

“…The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has also published guidelines for the validation of methods for analysing impurities in new drug substances and drug products, residual solvents, and microbiological impurities [ 1 , 2 ]. ICH defines an impurity as “any chemical compound of the medicinal product which is not the chemical entity defined as the active substance or as an excipient in the product.” According to its guidelines, the threshold limit for any impurity is at 0.1% for drugs used in dosages more than 2 g/day and for those dosed at less than 2 g/day, the limit is below 0.05% [ 2 , 6 , 6 ]. If the structure and physical-chemical data-related information are available about the impurities, several spectroscopic and microchemical techniques have been developed which require minute quantities of material and readily enable the structural elucidation of the impurities.…”